Raising the Bar for Antidepressant Treatments - 2007

It wasn’t long ago that the modern crop of antidepressant medications–the selective serotonin-reuptake inhibitors (SSRIs) and similar drugs–was heralded as a breakthrough in the treatment of depression. These “second-generation” antidepressants, beginning with fluoxetine (Prozac®) in 1988, offered hope that the vast majority of depression sufferers could overcome the darkness that enshrouded them and retake control of their lives, simply by taking a pill. Clinical trials in the 1980’s and 1990’s, most of them run by drug companies seeking marketing approval, seemed to suggest that 80 to 90 percent of patients could be treated effectively, given enough time and diligent medical care.

Unfortunately, such results have not been borne out in practice. In the past year, data from the largest federally funded efficacy trial comparing various antidepressant regimens–the so-called STAR*D trial–have told a different story. STAR*D, an acronym for Sequenced Treatment Alternatives to Relieve Depression, was initiated and funded by the federal National Institute of Mental Health (NIMH) in an attempt to assess “real-world” scenarios for depression treatment, enrolling patients who are broadly representative of the actual population of people with depression as opposed to the carefully selected patient populations typically enrolled in pharmaceutical trials.

Even with the best care, STAR*D researchers found that only about 30 percent of people achieved remission, defined as the absence of all or most depressive symptoms, after an average of about seven weeks on a “first line” of antidepressant therapy. A second layer of treatment–adding another drug, switching drugs, or adding psychological therapy–helped an additional 30 percent of people who didn’t respond to first-line treatment. Each additional layer of treatment helped another 10 to 15 percent of nonresponders, reaching a cumulative remission rate of 50 to 60 percent after persistent, aggressive treatment.

A report released in January by the Agency for Healthcare Research and Quality echoed these results, finding from a review of nearly 300 published studies that 38 percent of patients saw no improvement on second-generation antidepressants and 54 percent had only partial improvement. Six in 10 adult patients experienced at least one side effect, ranging from nausea to sexual dysfunction.

Further complicating treatment, there is apparently a small but real increased risk for suicide among younger patients taking antidepressant medications. In 2004, the Food and Drug Administration required drug makers to add “black-box” warnings on drug labels based on data suggesting that children and adolescents taking the drugs have an increased incidence of suicidal behavior, encompassing thoughts, attempts, or completed suicide. In December 2006, an FDA advisory committee concluded that the risk extended to young adults up to age 25; the agency issued a public health advisory cautioning patients and physicians of the danger and is considering further label changes.

“It’s now apparent that the drugs we have available currently for depression are–how shall I say–a little more discouraging than we might have expected five years ago,” says NIMH Director Thomas R. Insel, who is a member of the Dana Alliance for Brain Initiatives. “Be it antidepressant medications or any of the psychotherapy approaches that are known to be effective in depression, virtually all of today’s treatments take several weeks to work, and they work only in somewhere between 30 and 70 percent of people, depending on how you define the response. That’s better than placebo, but it still leaves a lot of people who aren’t responding.”

A member of the Dana Alliance and the Dana Foundation Board, Steven Hyman, who was NIMH director prior to Insel and is now provost of Harvard University, says the STAR*D trial underscores the need for other approaches to treating depression. “If you look at the STAR*D results, you can see that SSRI’s and SNRI’s (serotonin and norepinephrine reuptake inhibitors) in aggregate are effective, to be sure, but only moderately so, and that many people have significant residual symptoms even with the best treatment. We desperately need better drugs.”

Limited Options for Short Term

Given all this, what is the future of depression treatment? What alternatives to current antidepressants do patients have?

“I think we’re in a rather difficult place right now,” says Hyman. “There’s nothing for next week, or even for next year, unless some drug company has something we don’t know about yet.”

Part of the reason for the dearth of new antidepressants in the pipeline, experts say, is that Big Pharma has tended to focus on tweaking current drug formulas as opposed to developing new classes of molecules, pumping out “new and improved” versions of existing drugs that may be longer-lasting or have different side effect profiles. SNRI’s like venlafaxine (Effexor®) and other drugs that target the neurotransmitter norepinephrine as well as serotonin were developed based on this strategy.

It’s a strategy that has largely failed to move depression treatment forward, as evidenced by the AHRQ report’s finding that newer antidepressants are no more effective than older ones and cause a similar overall burden of side effects, though the types of adverse events differ significantly by drug.

“I think the field has been constrained by simply focusing on the medications we now have and figuring out how to slightly improve them,” says Insel. “That might not get us where we want to be.”

Psychotherapeutic strategies, including cognitive behavioral therapy and interpersonal therapy, have proven effectiveness in depression, but are apparently underutilized. The STAR*D trial suggested that the inconvenience of such therapies was a primary barrier, as they must be administered by psychiatrists trained in specific techniques. As such, they add another layer of complexity (and co-payments) to the treatment of an illness marked by motivational symptoms and fatigue.

For patients who do not respond to antidepressants or cognitive therapy, a surgical technique called vagus nerve stimulation (VNS) was approved by the FDA in 2005. VNS uses electrical impulses generated by a device implanted in the chest to stimulate the vagus nerve, the primary communication pathway connecting the brain to major organs of the body. But VNS is expensive, requires major surgery, and its effectiveness remains controversial, given that the only efficacy studies on the technique have been conducted by the company that sells the device. Many experts are withholding judgment on VNS until more data, from independent labs, can prove its efficacy.

Longer Term Promising

If the short-term prospects for better depression treatments are somewhat bleak, the long-term outlook is promising in contrast. Insel points to two developments reported by NIMH researchers in the past year that he considers “breakthrough reports that are intriguing because they tell you that it is possible to treat this illness very differently than with the medications we now have.”

The first focuses on ketamine, a medication currently used in higher doses as an anesthetic for humans and animals. Researchers led by Carlos Zarate of NIMH reported in August that people with treatment-resistant depression experienced relief of symptoms in as little as two hours with a single intravenous dose of ketamine. Twenty-nine percent of the study participants achieved remission within one day, and 71 percent experienced significant improvement in symptoms. About a third of the patients still showed benefits seven days later.

The second report, from NIMH researchers Maura Furey and Wayne Drevets, showed similar dramatic improvements with a single intravenous dose of scopolamine, a commonly used sedative and motion-sickness drug. While small in size, the study found that 10 of the 18 patients who completed the trial achieved remission of depression, and 11 more experienced at least a 50 percent reduction in symptoms. The NIMH has initiated a second-phase trial of a scopolamine skin patch in a larger sample of patients.

Neither scopolamine nor ketamine are expected to become standard treatments for depression, but they have generated excitement because they point the way to the development of fast-acting, effective antidepressants.

“These reports are proof of principle that we can be thinking about other kinds of medications that have a target of affecting depression not over six to 12 weeks, but in six to 12 hours,” says Insel. “They demonstrate that we can really change the expectation here, to raise the bar of what we want these medications to do and think about new classes of compounds.”

Both drugs work completely differently than any antidepressant on the market. Ketamine blocks NMDA receptors, which are critical to glutamate signaling, a neurotransmitter that enhances electrical flow among nerve cells. Other studies have suggested that glutamate dysregulation may be one factor in the pathophysiology of depression.

Scopolamine is an anticholinergic medication that blocks nerve cell responses to acetylcholine, a neurotransmitter implicated in cognition and mood. A previous clinical trial of a different anticholinergic, biperiden, failed to demonstrate a benefit in depression, so it is unclear whether this mechanism underlies scopolamine’s antidepressant activity, or if some other action is involved. NIMH is conducting further studies.

Going Deeper for a Cure

Another novel treatment strategy that is attracting attention is Deep Brain Stimulation (DBS), a surgical approach along the lines of VNS. Rather than stimulating the vagus nerve, DBS targets a neural circuit running through a specific region of the prefrontal cortex, known as Area 25. So far, DBS has been used only in a relatively small number of people whose depression has not responded to any other treatment, but the results have been dramatic.

“When you activate the white matter tracts around Area 25 in people with really severe refractory depression, they have an immediate response as soon as you turn on the current,” says Insel. “DBS is not a cure, but it certainly makes these people much, much better–better than they were on any medication. They are able to return to work and get on with life.”

Insel is particularly enthused about the DBS results because they “not only demonstrate that depression is a brain disease, but that the same kind of approach that has worked so well in Parkinson’s disease may work equally well–or even better–in depression.”

Such demonstrations are critical to moving the field of depression therapy forward, Insel says, because they “redefine the problem” and focus attention on the goal of curing the condition, as opposed to the partial mitigation of symptoms that is the current standard of care.

“In a sense this field has been cursed by having treatments that work pretty well. These drugs are not miracles, but they help, and people have just been satisfied with developing slightly better versions of these medications,” Insel says. “We haven’t had the same ambitions as we might have for say, cancer or heart disease, and there’s no excuse for that. There’s no reason to treat mental illnesses any differently than we treat other medical illnesses.”

“We need to find a way to really focus on the cure, on something that has a much more profound effect, with remission as the goal,” he adds. “If you are convinced that this is a brain illness with significant genetic components that set up a pattern of risk, you can then bring to bear the tools of neuroscience to try to figure out how to cure it.”